Trifluoroacetic acid-mediated facile construction of 6-substituted phenanthridines

Article abstract of DOI:10.1016/j.tetlet.2009.05.071

The trifluoroacetic acid-mediated reaction of 2-arylanilines with arylaldehydes has been developed to give a variety of 6-substituted phenanthridines. This is a very simple and convenient one-pot process for library construction.

Full text of DOI:10.1016/j.tetlet.2009.05.071

Tetrahedron Letters 50 (2009) 4598–4601
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Trifluoroacetic acid-mediated facile construction of 6-substituted
phenanthridines
*
So Won Youn , Joon Hyung Bihn
Department of Chemistry, Pukyong National University, Busan 608-737, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The trifluoroacetic acid-mediated reaction of 2-arylanilines with arylaldehydes has been developed to
give a variety of 6-substituted phenanthridines. This is a very simple and convenient one-pot process
for library construction.
Received 8 April 2009
Revised 18 May 2009
Accepted 21 May 2009
Available online 25 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Phenanthridines have attracted considerable attention in
medicinal chemistry and in material science due to their biological
activity and their presence in a variety of significant natural prod-
ucts and synthetic dye-stuffs.1 Consequently, a number of syn-
thetic strategies have been reported for the construction of
phenanthridines. However, multistep reactions,2d–g the limited
substrate scope, and frequent requirement of harsh reaction condi-
tions (e.g., P4O10, POCl3, or PCl5 at elevated temperature),2a–c extre-
mely high temperature (200–300 °C),2l anhydrous conditions,2e,f
air-sensitive organometallic reagents,2e,f or metal catalysis2g–k lim-
it the usefulness and generality of these methods.2 Therefore, there
is great demand to develop simple, convenient protocol for the
expeditious synthesis of phenanthridine derivatives.
In parallel with our efforts to develop new synthetic methods of
heterocycles,3 we were interested in developing a more versatile
and simpler one-pot synthesis of phenanthridines from 2-arylani-
lines and aldehydes via sequential C–N and C–C bond formations
with high efficiency (Scheme 1). Herein we report the trifluoroace-
tic acid (TFA)-mediated coupling reaction of 2-arylanilines with
arylaldehydes for the direct synthesis of phenanthridines in a
one-pot process.2o
sequential deprotection/aromatization (Table 1, entries 1 and 2).
Then, the same reaction was performed in TFA in the absence of
Pd(OAc)2 and oxidant. Almost the same result was obtained, which
suggests that Pd(OAc)2 is not essential in this reaction (Table 1, en-
try 3 vs entries 1 and 2). HCl, H2SO4, and mixture of TFA and H2O
were ineffective, while AcOH, propionic acid, and mixture of TFA
and organic solvents such as CH2Cl2 and toluene gave lower con-
version than only TFA (Table 1, entries 4–13). These results suggest
that TFA plays a dual role of catalyst and solvent in this coupling
process.5 Both lowering reaction temperature and short reaction
time decreased the yield of 2a dramatically (Table 1, entries
14–17).
With the establishment of a one-pot transformation of Ts-biaryl
amide (1a) to 6-phenylphenanthridine (2a), we turned our atten-
tion to substrates containing other amine protecting groups.
2-Aminobiphenyl protected as other amides such as acetamide
(1b), methanesulfonamide (1c), benzamide (1d), and tert-butyl-
carboxycarbonylamide (Boc-amide, 1e) provided much lower
yields of the desired products (Table 1, entries 18–21). In contrast,
2-phenylaniline itself (1f) did result in the production of 2a as effi-
ciently as the corresponding Ts-amide (1a) (Table 1, entry 22). Re-
cently, the modified Pictet-Spengler reaction involving 2-(2-
aminopyrimidin-4-yl)aniline derivatives has been reported in
which the presence of amino substituent on pyrimidine moiety
2-Phenylanilines such as N-Ts-2-phenylaniline4a and N-Ac-2-
phenylaniline4b are known to undergo C–H bond activation and
C–C or C–N bond formations in the presence of Pd(II) catalysts.
Therefore, we envisioned that Pd(II)-catalyzed C–H bond function-
alization of 2-phenylaniline derivatives with aldehydes could af-
ford dihydrophenanthridines. First, we examined the reaction of
N-Ts-2-phenylaniline (1a) and benzaldehyde in TFA in the pres-
ence of Pd(OAc)2 (5 mol %) and oxidants (benzoquinone (BQ) or
Cu(OAc)2). When reaction mixture was heated at 120 °C for 35 h,
6-phenylphenanthridine (2a) was obtained in good yields, instead
of the corresponding 5,6-dihydrophenanthridine derivative, via
may serve as an electron–donating group to facilitate p–cyclization
in the presence of strong Brønsted acid such as triflic acid.6 Since
R
NHR
N
N
or
+ R'CHO
R'
R'
* Corresponding author. Tel.: +82 51 629 5594; fax: +82 51 629 5583.
E-mail addresses: sowony@pknu.ac.kr, so_wony@hotmail.com (S.W. Youn).
Scheme 1. One-pot synthesis of phenanthridines from 2-arylanilines and alde-
hydes via sequential C–C/C–N bond formations.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.071

S. W. Youn, J. H. Bihn / Tetrahedron Letters 50 (2009) 4598–4601
4599
Table 1
Table 2
Optimization studies for the synthesis of 6-phenylphenanthridinea
Synthesis of 6-substituted phenanthridines by TFA-mediated reaction of 2-arylani-
lines with arylaldehydesa
Entry Substrate
Aldehyde
PhCHO
Product
Yieldb (%)
NHR
N
+ PhCHO
N
NH2
1
2
3
91
1
2a
1f
Entry
R
Solvent
Yieldb (%)
2a
1c
2d
3
4
5
6
7
8
9
10
11
12
13
14g
15h
16i
17j
18
19
20
21
22
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ts (1a)
Ac (1b)
Ms (1c)
Bz (1d)
Boc (1e)
H (1f)
TFA
TFA
TFA
AcOH
CH3CH2CO2H
60
88
80
15
45
70
50
60
15
—
N
NH2
4-MeC6H4CHO
90
75
1f
TFA/CH2Cl2 (2/1)
TFA/CH2Cl2 (1/1)
TFA/CH2Cl2 (1/2)
TFA/CH2Cl2 (1/4)
TFA/H2O (2/1)
2b
N
TFA/toluene (2/1)
50
—
—
NH2
4-
e
H2SO4
MeOC6H4CHO
HClf
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
1f
40
10
30
20
50
40
50
50
85
OMe
2c
N
NH2
4
4-
68
NO2C6H4CHO
1f
2d
NO2
a
Reaction conditions: 1 (1 equiv), PhCHO (2 equiv), solvent (0.1 M), 120 °C, 35 h,
unless otherwise noted.
b
Determined by 1H NMR using trichloroethylene as an internal standard.
Performed in the presence of 5 mol % of Pd(OAc)2 and 2 equiv of BQ.
Performed in the presence of 5 mol % of Pd(OAc)2 and 2 equiv of Cu(OAc)2.
Concd H2SO4 (98%).
Aq HCl (37%).
Performed at 100 °C.
Performed at 80 °C.
Performed for 24 h.
c
d
N
Br
e
NH2
5
6
2-BrC6H4CHO
74
70
f
g
1f
h
2e
i
j
Performed for 12 h.
N
NH2
PhCHO
there is no need for prefunctionalization (e.g., protection of amine
or imine synthesis) for practical purposes, we focused on the reac-
tion of free amine substrates with aldehydes in TFA.
1g
MeO
MeO
2f
We set out to explore the scope of this process. As shown in
Table 2, a variety of 2-arylanilines and arylaldehydes underwent
coupling reaction in TFA to form the corresponding phenanthri-
dines.7 Both electron-rich and electron-deficient arylaldehydes as
well as sterically hindered arylaldehyde were all successful in this
NH2
N
7
PhCHO
59
1h
reaction (Table 2, entries 1–5). However, heteroarylaldehydes, a,b-
unsaturated aldehydes, and alkylaldehydes led to a complicated
mixture and only a small amount of the desired products (<30%).
We proceeded to examine the effects of substituents at the 2-
arylaniline moiety. A variety of substituted 2-arylanilines were
prepared by the Suzuki–Miyaura coupling reaction of 2-bromoan-
iline and appropriate arylboronic acids (Scheme 2). Both electronic
and steric effects of substituents in the 2-phenyl ring (bottom ring)
seem to influence the efficiency of the coupling reaction. Ortho
substitution to the biaryl axis hampered the reactions (Table 2, en-
try 8). Compared to the substrate with methoxy substituent at para
position to the biaryl axis, meta-substituted one showed enhanced
reactivity (Table 2, entries 6 and 7). Furthermore, both 2-(3-nitro-
phenyl)aniline and 2-(4-chlorophenyl)aniline did not undergo con-
version to the corresponding phenanthridines. Taking these results
into consideration, it is likely that this reaction proceeds through
an electrophilic pathway involving imine activation by acid, imin-
ium ion (Fig. 1).2o,6,8 It should be noted that the cyclization reaction
2g
OMe
OMe
N
NH2
8
PhCHO
23
MeO
MeO
1i
2h
N
NH2
9
PhCHO
79
1j
MeO
MeO
2i
(continued on next page)

4600
S. W. Youn, J. H. Bihn / Tetrahedron Letters 50 (2009) 4598–4601
9). Coupling at the more hindered carbon was not observed. 2-
Table 2 (continued)
(1-Naphthyl)aniline also underwent the coupling reaction in good
yields (Table 2, entry 12). In addition, 2-heteroarylanilines (Table 2,
entries 14 and 15) and 2-cinnamylaniline (Table 2, entry 13)
proved to be suitable substrates, affording the corresponding quin-
oline derivatives.
Entry Substrate
Aldehyde
PhCHO
Product
Yieldb (%)
NH2
N
10
86
In summary, we have developed a simple and convenient one-
pot procedure, TFA-mediated reaction of 2-arylanilines with arylal-
dehydes to afford 6-substituted phenanthridines. The fact that this
process can tolerate various functional groups such as methoxy,
bromo, nitro, furyl, and thienyl groups is noteworthy. All 6-aryl-
substituted phenanthridines prepared from this facile reaction
were highly fluorescent and will have important applications in
material science and as DNA-intercalating agents. While limitation
of this process includes the requirement of harsh reaction condi-
tions (in TFA at 120–140 °C for 1.5–7 days) and a specific substrate
class (such as arylaldehydes), the operational simplicity and use of
simple reactants without requirement of synthesis of complicated
precursors, strictly anhydrous conditions, air-sensitive organome-
tallic reagents, or expensive metal catalysts make it particularly
attractive for library construction of fluorescent molecules, which
could be directly utilized for DNA-sequencing.
1k
2j
NH2
1l
N
11
12
13
14
15
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
64
83
59
45
20
2k
N
NH2
1m
2l
NH2
N
Acknowledgments
This work was supported by the Korea Research Foundation
Grant (KRF-2006-331-C00168) and by the Korea Science and Engi-
neering Foundation (KOSEF) grant (No. R01-2008-000-20332-0)
funded by the Korea government. We are grateful to BK21 Founda-
tion for generous support.
1n
2m
N
NH2
S
Supplementary data
S
1o
2n
Supplementary data (full experimental details, characterization
data of substrates and products, and copies of 1H, 13C NMR spectra
of all products) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2009.05.071.
N
NH2
O
1p
O
2o
References and notes
a
Reaction conditions: 1 (1 equiv), aldehyde (2 equiv), TFA (0.1 M), 120–140 °C,
1.5–7 days.
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71, 9241; (o) Very recently, a similar result for the synthesis of phenanthridines
was published. And it was described that the strategy is based on the modified
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Org. Biomol. Chem. DOI: 10.1039/b905696c.
R
R
10 mol % PdCl2(PPh3)2
+ ArB(OH)2
NH2
NH2
DMF/H2O (5/1)
Br
K2CO3, 80 oC, 24 h
Ar
R = H, Me
1
61-98%
Scheme 2. Synthesis of various 2-arylanilines by the Suzuki–Miyaura coupling
reaction.
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CF3CO2
H
N
R
R'
Figure 1. Possible mechanism.

S. W. Youn, J. H. Bihn / Tetrahedron Letters 50 (2009) 4598–4601
4601
5. For selected examples of TFA-mediated coupling reactions, see: (a) Li, K.;
Foresee, L. N.; Tunge, J. A. J. Org. Chem. 2005, 70, 2881; (b) Wu, Y.-C.; Liu, L.; Liu,
Y.-L.; Wang, D.; Chen, Y.-J. J. Org. Chem. 2007, 72, 9383; (c) Cincinelli, R.;
Dallavalle, S.; Merlini, L. Synlett 2008, 1309; (d) Augustine, J. K.; Naik, Y. A.;
Mandal, A. B.; Alagarsamy, P.; Akabote, V. Synlett 2008, 2429; (e) Che, X.; Zheng,
L.; Dang, Q.; Bai, X. J. Org. Chem. 2008, 73, 1147.
6. Agarwal, P. K.; Sharma, S. K.; Sawant, D.; Kundu, B. Tetrahedron 2009, 65, 1153.
7. General procedure for the synthesis of 6-substituted phenanthridines by TFA-
mediated reaction of 2-arylanilines and arylaldehydes: To a solution of 2-
arylaniline 1 in TFA (0.1 M) in a pressure tube was added arylaldehyde (2 equiv).
The pressure tube was tightly capped and the resulting mixture was heated with
stirring at the reported temperature (120–140 °C) for the reported time. After
the reaction was completed, the solvent was blown off with Ar and the residue
was diluted with CH2Cl2, basified with satd NaHCO3, extracted with CH2Cl2
(three times), washed with brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel (EtOAc/n-
hexane = 1:8–1:30) to give the corresponding product 2.
8. One referee suggested that 1,6-electrocyclization of azatriene systems should be
used as the key word to explain the plausible mechanism and we agree that this
cannot be excluded.